Drug Repurposing to Accelerate Progress in Neonatal Neuroprotection

药物再利用加速新生儿神经保护的进展

• 批准号: 10454287
• 负责人: JOHN D BARKS
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454287
• 关键词: Acute Brain Injuries; Address; Adolescent; Adverse effects; Advocate; Age; Agonist; Animal Model; Animals; Antibiotics; Attenuated; Azithromycin; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Caffeine; Carotid Arteries; Cessation of life; Childhood; Clinical; Clinical Trials; Cognitive deficits; Complex; Consultations; Contralateral; Corpus striatum structure; Data; Development; Dose; Ensure; Erythropoietin; Evaluation; Event; Experimental Animal Model; Exposure to; FDA approved; Funding; Goals; Hippocampus (Brain); Histopathology; Human; Hypoxia; Hypoxic-Ischemic Brain Injury; Infant; Infarction; Infection; Inflammation; Inflammatory; Injections; Injury; Intervention; Ipsilateral; Ischemia; Laboratories; Lesion; Life; Ligation; Lipopolysaccharides; Mammals; Measures; Melatonin; Memory; Methods; Modeling; Morbidity - disease rate; Necrotizing Enterocolitis; Neonatal; Neonatal Brain Injury; Neurologic; Neurologic Deficit; Neuroprotective Agents; Outcome; Outcome Measure; Oxygen; Pathology; Perinatal Brain Injury; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase III Clinical Trials; Premature Infant; Probability; Procedures; Property; Prosencephalon; Protocols documentation; Publications; Rattus; Regimen; Reperfusion Therapy; Reporting; Research; Research Personnel; Risk; Rodent; Rodent Model; Safety; Sample Size; Sensorimotor functions; Severities; Side; Standardization; Stimulus; Survivors; TLR2 gene; TLR4 gene; Tetracyclines; Therapeutic; Time; Tissues; age group; base; brain tissue; clinical efficacy; comparative efficacy; design; disability; drug candidate; drug development; drug repurposing; efficacy study; efficacy testing; experimental study; functional outcomes; improved; intraamniotic infection; intrauterine infection; ischemic injury; model design; natural hypothermia; neonatal brain; neonatal human; neonatal hypoxic-ischemic brain injury; neonatal infection; neonatal period; neonatal resuscitation; neonate; neuropathology; neuroprotection; novel strategies; novel therapeutics; perinatal injury; postnatal; premature; preterm newborn; primary outcome; protective efficacy; response; sildenafil; stem; topiramate; white matter; white matter injury

Abstract In childhood, the risks of acute brain injury peak in the neonatal period. Major mechanisms of perinatal brain injury include hypoxia-ischemia (HI) and inflammation in response to intrauterine (e.g. chorioamnionitis) or neonatal (e.g. necrotizing enterocolitis) infections. In term infants, antecedent hypoxic-ischemic events can often be discerned; in premature neonates, multifactorial contributing mechanisms are often more difficult to identify. In view of the significant neurologic morbidity associated with perinatal brain injury in both term and preterm infants, effective neuroprotective interventions are greatly needed. Many drugs decrease brain injury and improve functional outcome in neonatal rodent hypoxic-ischemic (HI) brain injury models. A major translational challenge is to select those to prioritize for advancement to complementary larger animal perinatal injury models, and ultimately to early stage human neonatal trials. In view of the time lag from new drug development to clinical trials, our strategy is to prioritize evaluation of potentially neuroprotective drugs that are already approved for other indications i.e. “repurposing”, and utilize an “adaptive platform design model” for comparative efficacy studies. This proposal builds upon our recent findings that treatment with a clinically available antibiotic, azithromycin (AZ), reduces brain damage and improves functional outcomes in multiple neonatal rodent hypoxic-ischemic (HI) brain injury models. Our aims are to compare neuroprotective efficacy among clinically available drugs, including AZ, that are neuroprotective in similar neonatal rodent models, to help prioritize the best candidate(s) to advance to human trials. Efficacy will be compared in well-characterized rat models of hypoxic-ischemic and inflammation-amplified hypoxic-ischemic brain injury. We will incorporate studies in two age groups, post-natal day 7 (P7), to model term brain development, and P3, to model premature neonates. To elicit unilateral forebrain injury, animals undergo unilateral carotid artery ligation and subsequent timed (45-90 min) exposure to 8% oxygen; this results in quantifiable sensorimotor deficits and unilateral brain tissue damage. Pro-inflammatory stimuli, e.g. injections of a TLR-4 (lipopolysaccharide, LPS) or a TLR-2 (Pam3CSK4) agonist prior to lesioning, amplify HI injury. Our preliminary studies showed that treatment with AZ confers dose and time-dependent neuroprotection, at both ages, vs. HI and inflammation- amplified HI injury. Our current goals are to compare the neuroprotective efficacy among multiple clinically available drugs (AZ, erythropoietin, melatonin, sildenafil, caffeine, topiramate) in P7 (Aim 1) and P3 (Aim 2) rat hypoxic-ischemic and inflammation-amplified hypoxic-ischemic brain injury models. We quantify protective efficacy with composite scores that incorporate lateralizing sensorimotor function, memory and neuropathology measures, and also account for death as a possible injury outcome. We hypothesize that these comparative efficacy studies will identify one or two drugs with the highest probability of superiority at each age, and thus accelerate progress towards advancing safe and effective drugs to clinical trials in term and preterm neonates.

抽象的 在儿童时期，急性脑损伤在新生儿时期达到峰值。围产期大脑的主要机制 损伤包括缺氧 - 缺血（HI）和炎症，响应宫内（例如绒毛膜炎）或 新生儿（例如坏死性小肠结肠炎）感染。在术语婴儿中，先前的低氧缺血性事件可以 经常被辨别；在过早的新生儿中，多因素的贡献机制通常更难 确认。鉴于与期限和 早产婴儿，有效的神经保护干预措施非常需要。许多药物减少了脑损伤 并改善新生儿啮齿动物缺氧缺血（HI）脑损伤模型的功能结果。专业 翻译挑战是选择要优先级以促进的挑战以完成更大的动物围产期 伤害模型，最终到早期人类新生儿试验。鉴于新药的时间滞后 开发临床试验，我们的策略是优先评估潜在的神经保护药物 已经批准了其他指示，即“重新调整”，并使用“自适应平台设计模型” 比较效率研究。这项提案是基于我们最近的发现，即临床治疗 可用的抗生素，阿奇霉素（AZ），可减少脑损伤并改善多种功能结果 新生儿啮齿动物缺氧 - 缺血（HI）脑损伤模型。我们的目的是比较神经保护效率 在包括AZ在内的临床可用药物中，在类似的新生儿啮齿动物模型中具有神经保护作用 帮助优先考虑最佳候选人，以促进人类试验。特征良好的功效将进行比较 低氧缺血和炎症的低氧缺血性脑损伤的大鼠模型。我们将合并 在两个年龄段的第7天（P7）中进行的研究，以模拟术语脑发育和P3，以建模 过早的新生儿。为了引起单方面的前脑损伤，动物经历了单侧颈动脉结扎和 随后的时间（45-90分钟）暴露于8％的氧气；这导致可量化的感觉运动定义，并 单侧脑组织损伤。促炎性刺激，例如注射TLR-4（脂多糖，LPS） 或在病变之前的TLR-2（PAM3CSK4）激动剂，放大HI损伤。我们的初步研究表明 AZ贡献的治疗剂量和时间依赖性神经保护在两个年龄，HI和炎症 - 放大的HI受伤。我们目前的目标是比较多个临床上的神经保护效率 P7（AIM 1）和P3（AIM 2）大鼠的可用药物（AZ，促红细胞生成素，褪黑激素，西地那非，咖啡因，topramate） 缺氧 - 缺血性和炎症的缺氧缺血性脑损伤模型。我们量化受保护 效率的复合分数融合了侧向感觉运动功能，记忆和神经病理学的效率 措施，也将死亡视为可能的伤害结果。我们假设这些比较 疗效研究将确定每个年龄段最高概率的一种或两种药物，因此 加速进步，将安全有效的药物推进到期限和早产新生儿的临床试验。